This invention is directed to methods for treatment of disease-induced peripheral neuropathy and related conditions, particularly with purine derivatives or analogues, tetrahydroindolone derivatives or analogues, or pyrimidine derivatives or analogues.
Although methods have improved for the treatment of diabetes and its consequences, diabetic neuropathy is still an extremely serious problem. Diabetic neuropathy can be defined as a demonstrable disorder, either clinically evident or subclinical, that occurs in the setting of diabetes mellitus without other causes for peripheral neuropathy. The neuropathic disorder includes manifestations in the somatic and/or autonomic parts of the peripheral nervous system. Diabetic neuropathy often is associated with damage to the nerves just under the skin leading to one or more of the following conditions: numbness and tingling of fingers, hands, toes, and feet; weakness in hands and feet; or pain and/or burning sensation in hands and feet. Nerve damage as the result of peripheral neuropathy can also lead to problems with the GI tract, heart, and sexual organs, causing indigestion, diarrhea or constipation, dizziness, bladder infections, and impotence.
Diabetic neuropathy is one example of disease-induced peripheral neuropathy, which has other causes. Similar neuropathies can occur in conditions such as acromegaly, hypothyroidism, AIDS, leprosy, Lyme disease, systemic lupus erythematosus, rheumatoid arthritis, Sjxc3x6gren""s syndrome, periarteritis nodosa, Wegener""s granulomatosis, cranial arteritis, and sarcoidosis, among other conditions.
More than 15% of the 13 million diabetic patients in the United States suffer symptomatic disturbances to the nervous system. Significant clinical neuropathy can develop within the first 10 years after diagnosis of diabetes and the risk of developing neuropathy increases the longer a person has diabetes. Although in most cases (30-40%) there are no symptoms, up to 60% of patients with diabetes have some form of neuropathy. Diabetic neuropathy appears to be more common in smokers, people over 40, and those who have had problems controlling their blood glucose levels.
There are currently no drugs on the market for the treatment of diabetic neuropathy. There are some drugs in trials or awaiting trials, including alond (zopolrestat; Pfizer), zenarestat (Fujisawa), pregabalin (Warner-Lambert), timcodar dimesylate (Vertex), the NMDA antagonist memantine (Merz), neurulin (Cortec), and an IGF-II product (Aurogen).
Other approaches are being tried or being considered, including aldose reductase inhibitors, which are thought to inhibit the increased flux through the polyol pathway caused by high blood glucose, mimicking the effect of improved glycemic control, nerve growth factor, alpha-lipoic acid, gamma-linolenic acid as a food supplement, insulin-like growth factor hormones, immunoglobulin, myo-inositol, or aminoguanidine.
However, there is still a substantial need for an improved treatment for diabetic neuropathy, particularly a treatment that can actually slow or reverse the degeneration of the nerves involved without inducing hyperalgesia.
Therefore, there exists a need for improved methods for treating diabetic neuropathy as well as other disease-induced peripheral neuropathies. There is a particular need for methods that can stimulate nerve growth or regeneration, particularly without inducing hyperalgesia.
One embodiment of the present invention is a method of treating disease-induced peripheral neuropathy comprising administering to a patient with peripheral neuropathy an effective quantity of an effective quantity of a compound comprising: (1) a moiety A selected from the group consisting of a purine moiety, a purine analogue, a tetrahydroindolone moiety, a tetrahydroindolone analogue, a pyrimidine moiety, and a pyrimidine analogue; (2) a hydrocarbyl moiety L of 1 to 6 carbon atoms that is linked to the moiety A and that can be cyclic, with the hydrocarbyl moiety being optionally substituted with one or more substituents selected from the group consisting of lower alkyl, amino, hydroxy, lower alkoxy, lower alkylamino, lower alkylthio, and oxo; and (3) a moiety B that is linked to the moiety L though a carbonyl group wherein B is xe2x80x94OZ or N(Y1)-D, where Z is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, aralkyl, or heteroaralkyl; D is a moiety that promotes absorption of the compound; and Y1 is hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms, which can be N, O, or S.
The purine moiety can be selected from the group consisting of hypoxanthine and guanine, as well as other purine moieties. A number of purine derivatives suitable for use in methods according to the present invention are disclosed. A particularly preferred purine derivative is N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide. Preferably, the compound is capable of passing through the blood-brain barrier.
Typically, the administration of the compound induces peripheral nerve sprouting in the skin of the patient to whom the purine derivative is administered. The peripheral nerve sprouting can be nociceptive nerve sprouting. Typically, the nociceptive nerve sprouting is induced without the occurrence of hyperalgesia. Additionally, methods according to the present invention can prevent large and small sensory nerve dysfunction in diabetes.
The disease-induced peripheral neuropathy can be diabetic neuropathy or can be a neuropathy associated with the following conditions: acromegaly, hypothyroidism, AIDS, leprosy, Lyme disease, systemic lupus erythematosus, rheumatoid arthritis, Sjxc3x6gren""s syndrome, periarteritis nodosa, Wegener""s granulomatosis, cranial arteritis, or sarcoidosis.